Articolo in rivista, 2017, ENG, 10.1016/j.ejmech.2016.12.036

Identification of new pyrrolo[2,3-d]pyrimidines as Src tyrosine kinase inhibitors in vitro active against Glioblastoma

Musumeci, Francesca; Fallacara, Anna Lucia; Brullo, Chiara; Grossi, Giancarlo; Botta, Lorenzo; Calandro, Pierpaolo; Chiariello, Mario; Kissova, Miroslava; Crespan, Emmanuele; Maga, Giovanni; Schenone, Silvia

Univ Genoa; Univ Siena; Univ Federico II Napoli; CNR; Ist Toscano Tumori; CNR IGM-CNR, Pavia

In the last few years, several pyrrolo-pyrimidine derivatives have been either approved by the US FDA and in other countries for the treatment of different diseases or are currently in phase clinical trials. Herein we present the synthesis and the characterization of a novel series of pyrrolo[2,3-d]pyrimidines, compounds 8a-j, and their activity against Glioblastoma multiforme (GBM). Docking studies and MMGBSA analysis revealed the ability of such compounds to efficiently interact with the ATP binding site of Src. Enzymatic assays against a mini-panel of kinases (Src, Fyn, EGFR, Kit, Flt3, Abl, AbIT315I) have been performed, showing an unexpected selectivity of our pyrrolo[2,3-d]pyrimidines for Src. Finally, the derivatives were tested for their antiproliferative potency on U87 GBM cell line. Compound 8h showed a considerable cytotoxicity effect against U87 cell line with an IC50 value of 7.1 mu M. (C) 2016 Elsevier Masson SAS. All rights reserved.

European journal of medicinal chemistry 127 , pp. 369–378

Keywords

Pyrrolo-pyrimidines, Src, Glioblastoma, Kinase inhibitors, Small molecules

CNR authors

Chiariello Mario, Maga Giovanni, Crespan Emmanuele

CNR institutes

IFC – Istituto di fisiologia clinica, IGM – Istituto di genetica molecolare "Luigi Luca Cavalli Sforza"